Selective κ Opioid Receptor (KOPR) Antagonists, including the compound known as norBNI (nor-binaltorphimine), have been investigated for their therapeutic properties and used as tools in opioid research. norBNI and analogs thereof are considered to act as a bivalent ligand for KOPR, with the pyrrole acting essentially as a spacer.
Current methods for the chemical synthesis of norBNI and related compounds from, for example, naltrexone, proceed in two steps by Piloty synthesis. The first step involves the synthesis of the azine intermediate by reacting naltrexone with hydrazine, followed by change of solvent for conversion of the azine to norBNI. Portoghese P S et al., Binaltorphimine-Related Bivalent Ligands and Their κ Opioid Receptor Antagonist Selectivity, J. Med. Chem. 31:836-841 (1988). The yield of the reaction is low (e.g., 40-60%), and the process is not sufficiently scalable. Further, the known synthesis may produce reaction by-products with unintended pharmacological activity, or otherwise include potentially toxic impurities that are difficult to remove.
It is an object of the invention to provide improved methods for the chemical synthesis of norBNI and related compounds, as well as compositions of such active agents that are suitable for pharmaceutical use.